Common Technical Document Bisoprolol hemifumarate 10 mg tablets

Module 1 - Section 3.5 Core SPC, Labelling and Package Leaflet page 1/11

1.3.5 SUMMARY OF PRODUCT CHARACTERISTICS

1 Name of the medicinal product

Bisoprololfumaraat 10 mg, film-coated tablets

2 Qualitative and quantitative composition

Each tablet contains 10 mg Bisoprolol hemifumarate, equivalent to 8.49 mg of bisoprolol.

For a full list of excipients, see section 6.1.

3 Pharmaceutical form

Film-coated tablet.

The tablet is yellow to orange, round, biconvex, scored on both sides and embossed with "BSL10" on one side.

4 Clinical Particulars

4.1 Therapeutic indications

- Hypertension. - Chronic stable angina pectoris.

4.2 Posology and method of administration

Bisoprolol 10 mg tablets are for oral administration.

The dosage should be individually adjusted. It is recommended to start with the lowest possible dose. In some patients, 5 mg per day may be adequate. The usual dose is 10 mg once daily with a maximum recommended dose of 20 mg per day.

The tablets should be taken in the morning. They should be swallowed with liquid and should not be chewed.

issue date: 07-07-06 version: M135-01.BSL.tab10.023.02 approved: Common Technical Document Bisoprolol hemifumarate 10 mg tablets

Module 1 - Section 3.5 Core SPC, Labelling and Package Leaflet page 2/11

Patients with kidney impairment In patients with severe renal impairment, (creatinine clearance < 20ml/min) the dose should not exceed 10 mg once daily. This dosage may eventually be divided into halves.

Patients with severe liver impairment No dosage adjustment is required, however careful monitoring is advised

Elderly: No dosage adjustment is normally required. It is recommended to start with the lowest possible dose

Children under 12 years and adolescents: There is no paediatric experience with this medicine, therefore its use cannot be recommended

Discontinuation of treatment Treatment should not be stopped abruptly (see section 4.4 Special warnings and precautions for use). The dosage should be diminished slowly by a weekly halving of the dose.

4.3 Contraindications

– acute heart failure or during episodes of heart failure decompensation requiring i.v. inotropic therapy – cardiogenic shock – AV block of second or third degree (without a pacemaker) – sick sinus syndrome – sinoatrial block – bradycardia with less than 60 beats/min before start of therapy – hypotension (systolic blood pressure less than 100 mm Hg) – severe bronchial asthma or severe chronic obstructive pulmonary disease – late stages of peripheral arterial occlusive disease and Raynaud's syndrome – metabolic acidosis – hypersensitivity to bisoprolol or to one of the excipients listed. – untreated phaeochromocytoma (see also section 4.4). – combinations with floctafenine and sultopride (see also section 4.5)

4.4 Special warnings and precautions before use.

Other formulations of bisoprolol containing medicinal products are used in the treatment of chronic heart failure. The use of β-blocking agents in this indication needs a very cautious approach and should be started with a very strict titration phase. In this phase increments are necessary all of which are issue date: 07-07-06 version: M135-01.BSL.tab10.023.02 approved: Common Technical Document Bisoprolol hemifumarate 10 mg tablets

Module 1 - Section 3.5 Core SPC, Labelling and Package Leaflet page 3/11

not possible with the current medicinal product. This product should therefore not be used in the treatment of chronic heart failure.

The combination with amiodarone should be used with caution considering the risk of contractility automatism and conduction disorders (suppression of compensatory sympathetic reactions).

Combination of bisoprolol with calcium antagonists of the verapamil and diltiazem type, and with centrally-acting antihypertensive drugs is generally not recommended (see also section 4.5).

Bisoprolol must be used with caution in:

– bronchospasm (bronchial asthma, obstructive airways disease): In bronchial asthma or other chronic obstructive airway diseases, which may cause symptoms, bronchodilating therapy should be given concomitantly. Occasionally an increase of the airway resistance may occur in patients with asthma, therefore the dose of β2-stimulants may have to be increased. It is recommended to have a functional respiratory test done before the initiation of treatment. – concomitant treatment with anticholinesterastic drugs (including tacrine): AV conduction time and/or bradycardia may be increased (see also section 4.5) – concomitant treatment with anaesthetics: Attenuation of the reflex tachycardia and increase of the risk of hypotension (see also section 4.5). Continuation of β-blockade reduces the risk of arrhythmia during induction and intubation. The anaesthesiologist should be informed when the patient is receiving bisoprolol. – Iodated contrast products: Beta-blockers may impede the compensatory cardiovascular reactions associated with hypotension or shock induced by iodated contrast products. – diabetes mellitus with large fluctuations in blood glucose values; symptoms of hypoglycaemia can be masked. Blood glucose levels should be monitored during treatment with bisoprolol – thyrotoxicosis, adrenergic symptoms may be masked – strict fasting – ongoing desensitisation therapy As with other β-blocking agents bisoprolol may increase both the sensitivity towards allergens and the severity of anaphylactic reactions. Adrenaline treatment does not always give the expected therapeutic effect. Higher doses of epinephrine (adrenaline) may be necessary. – AV block of first degree – Printzmetal's angina: β-blocking agents may increase the number and duration of anginal attacks in patients with Printzmetal's angina. The use issue date: 07-07-06 version: M135-01.BSL.tab10.023.02 approved: Common Technical Document Bisoprolol hemifumarate 10 mg tablets

Module 1 - Section 3.5 Core SPC, Labelling and Package Leaflet page 4/11

of β-1 selective adrenoceptor blocking agents is possible in cases of mild forms and only in combination with a vasodilating agent. – peripheral circulatory disorders, such as Raynaud's phenomena and intermittent claudication: intensification of complaints might happen especially during start of therapy. – In patients with phaeochromocytoma (see section 4.3), bisoprolol must not be administered until after α-receptor blockade – pre-existing or existing psoriasis, bisoprolol should only be given after a thorough risk/ benefit assessment

The initiation of treatment with bisoprolol necessitates regular monitoring, especially when treating elderly patients. The cessation of therapy with bisoprolol should not be done abruptly unless clearly indicated. There is a risk of myocardial infarction and sudden death if the treatment is suddenly discontinued in patients with ischaemic heart disease. For more information please refer to section 4.2 Posology and method of administration

This medicinal product contains an active substance, which results in a positive test during antidoping controls.

4.5 Interactions with other medicinal products and other forms of interaction

Combinations contra-indicated – Floctafenine: ß-blockers may impede the compensatory cardiovascular reactions associated with hypotension or shock that may be induced by floctafenine – Sultopride: bisoprolol should not be concomitantly administered with sultopride since there is an increase risk of ventricular arrhythmia

Combinations not recommended – Calcium antagonists (verapamil, diltiazem, bepridil): negative influence on contractility, atrio-ventricular conduction and blood pressure (see also section 4.4). – Clonidine and other centrally-acting antihypertensive drugs, i.e. methyldopa, guanfacin, moxonidine, rilmenidine: Increased risk of "rebound hypertension" as well as exaggerated decrease in heart rate and cardiac conduction, including worsening the cardiac insufficiency. – Monoamine oxidase inhibitors (except MAO-B inhibitors): Enhanced hypotensive effect of the beta-blockers but also risk for hypertensive crisis.

issue date: 07-07-06 version: M135-01.BSL.tab10.023.02 approved: Common Technical Document Bisoprolol hemifumarate 10 mg tablets

Module 1 - Section 3.5 Core SPC, Labelling and Package Leaflet page 5/11

Combinations to be used with caution – Class I antiarrhythmic drugs (e.g. disopyramide, quinidine): effect on atrio-venticular conduction time may be potentiated and negative inotropic effect may be increased. (Strict clinical and ECG monitoring is required). – Class III antiarrhythmic drugs (e.g. amiodarone): effect on atrial conduction time may be potentiated (see section 4.4). – Calcium antagonists (dihydropyridine derivatives): increased risk of hypotension. In patients with latent heart failure concomitant use of β- blocking agents can lead to heart failure – Anticholinesterastic drugs (including tacrine): atrio-ventricular conduction time and/or bradycardia may be increased (see also section 4.4). – Other β-blocking agents, including eye-drops, have additive effects – Insulin and oral anti-diabetic drugs: intensification of blood sugar lowering effect. Blockade of β-adrenoreceptor may mask symptoms of hypoglycaemia. – Digitalis glycosides: reduction of heart rate, increase of atrio-ventricular conduction time. – Anaesthetic agents: attenuation of the reflex tachycardia and increased risk of hypotension (for further information on anaesthesia see also section 4.4). – NSAIDs: decrease of the antihypertensive effect (inhibition of vasodilatative prostaglandin by NSAID and water and sodium retention with pyrazolone NSAID). – Ergotamine derivatives: exacerbation of peripheral circulatory disturbances. – Beta-sympathomimetic agents (eg. Isoprenaline, dobutamine): combination with bisoprolol may reduce effects of both agents. – Tricyclic antidepressants, barbiturates, phenothiazines as well as other antihypertensive agent: increased blood pressure lowering effect. – Baclofene: increased antihypertensive activity – Amifostine: increased hypotensive activity.

Combinations to be considered – Mefloquine: increased risk of bradycardia. – Corticosteroids: decrease of antihypertensive effect due to water and sodium retention.

4.6 Pregnancy and lactation

Use during pregnancy: Bisoprolol has pharmacological effects that may cause harmful effects on pregnancy and/or the fetus/newborn. In general, β-adrenoceptor blocking issue date: 07-07-06 version: M135-01.BSL.tab10.023.02 approved: Common Technical Document Bisoprolol hemifumarate 10 mg tablets

Module 1 - Section 3.5 Core SPC, Labelling and Package Leaflet page 6/11

agents reduce placental perfusion, which has been associated with growth retardation, intrauterine death, abortion or early labour. Adverse reactions (e.g. hypoglycaemia, bradycardia) may occur in the fetus and newborn infant. If treatment with β-adrenoceptor blocking agents is necessary, β1- adrenoceptor blocking agents are preferable. Bisoprolol should not be used during pregnancy unless clearly necessary. If treatment with bisoprolol is considered necessary, the uteroplancental blood flow and fetal growth should be monitored. In case of harmful effects on pregnancy or the fetus alternative treatment should be considered. The newborn infant must be closely monitored. Symptoms of hypoglycaemia and bradycardia are generally to be expected within the first 3 days.

Use during lactation: It is not known whether bisoprolol is excreted in human milk. Therefore breastfeeding is not recommended during administration of bisoprolol.

4.7 Effect on ability to drive and use machines

In a study with coronary heart disease patients, bisoprolol did not impair driving performance. However, due to individual variations in reactions to the medicinal product, the ability to drive a vehicle or to operate machinery may be impaired. This should be considered particularly at start of the treatment and upon change of medication as well as in conjunction with alcohol.

4.8 Undesirable effects

The reported undesirable effects are generally attributable to the pharmacological properties of ß-blocking agents.

The following undesirable effects have been observed during treatment with bisoprolol with the following frequencies: common (>1/100, ≤ 1/10), uncommon (>1/1,000, ≤ 1/100), rare (>1/10,000, ≤ 1/1,000), very rare (≤1/10,000) including isolated reports

Nervous system disorders Common: Tiredness, exhaustion, dizziness, headache (especially at the beginning of the therapy, they are generally mild and often disappear within 1-2 weeks)

issue date: 07-07-06 version: M135-01.BSL.tab10.023.02 approved: Common Technical Document Bisoprolol hemifumarate 10 mg tablets

Module 1 - Section 3.5 Core SPC, Labelling and Package Leaflet page 7/11

Vascular disorders Common: Feeling of coldness or numbness of the extremities, Raynaud’s disease, increase of existing intermittent claudication Uncommon: orthostatic hypotension

Gastrointestinal disorders Common: Nausea, vomiting, diarrhoea, abdominal pain and constipation.

Psychiatric disorders Uncommon: Sleep disturbances, depression Rare: Nightmare, hallucinations

Cardiac disorders Uncommon: Bradycardia, AV-stimulus disturbances (slowed AV-conduction or increase of existing AV-block), worsening of heart failure

Respiratory, thoracic and mediastinal disorders Uncommon: Bronchospasm in patients with bronchial asthma or a history of obstructive airway disease

Musculoskeletal and connective tissue disorders Uncommon: Musular weakness and cramps, arthropathy

Ear and labyrinth disorders Rare: Hearing impairment

Skin and subcutaneous tissue disorders Rare: Hypersensitivity reactions (itching, flush, rash) Very rare: β-blocking agents may provoke or worsen psoriasis or induce psoriasis-like rash, alopeciaZ

Eye disorders Rare: Reduced tear flow (to be considered if the patient uses lenses) Very rare: Conjunctivitis

Hepatobiliary disorders Rare: Increased liver enzymes (ALAT, ASAT), hepatitis

Metabolism and nutrition disorders Rare: Increased triglycerides, hypoglycaemia

Reproductive system and breast disorders Rare: Potency disorders

issue date: 07-07-06 version: M135-01.BSL.tab10.023.02 approved: Common Technical Document Bisoprolol hemifumarate 10 mg tablets

Module 1 - Section 3.5 Core SPC, Labelling and Package Leaflet page 8/11

Immune system disorders Rare: the appearance of antinuclear antibodies with exceptional clinical symptoms such as lupus syndrome, which disappear upon cessation of treatment, allergic rhinitis.

4.9 Overdose

Symptoms and treatment of overdose The most common expected symptoms with overdosage of bisoprolol are bradycardia, hypotension, bronchospasm, acute cardiac insufficiency, conduction disorders and hypoglycaemia. In the case of overdosage, bisoprolol treatment should be stopped and supportive and symptomatic treatment should be provided. Resorption of bisoprolol in the gastrointestinal tract must be avoided; gastric lavage, or administration of adsorbents (i.e. activated charcoal), and a laxative agent (i.e. sodium sulphate) may be used. Respiration must be monitored and if necessary, artificial respiration should be initiated. Bronchospasm should be counteracted with bronchodilator therapy such as isoprenaline or ß2- sympathomimetic drugs. Cardiovascular complications should be treated symptomatically: AV-block (second or third degree) needs careful monitoring and be treated with isoprenaline infusion or transvenous cardiac pacemaker insertion. Bradycardia should be treated with intravenous atropine (or M-methyl-atropine). Fall in blood pressure or shock should be treated with plasma substituting agents and vasopressors. Hypoglycaemia can be treated with i.v.-glucose.

5 Pharmacological properties

5.1 Pharmacodynamic properties

Pharmacotherapeutic group Selective ß1-blocking agents, ATC code: C07 AB07

Mechanism of action Bisoprolol is a potent, highly ß1-selective-adrenoceptor blocking agent devoid of intrinsic sympathomimetic activity. As with other ß-blocking agents, the mode of action in hypertension is unclear. However, it is known that bisoprolol markedly depresses plasma renin activity.

In patients with angina, the blockade of ß-receptors reduces heart action and thus reduces oxygen demand.

Bisoprolol possesses similar local anaesthetic properties to propanolol.

issue date: 07-07-06 version: M135-01.BSL.tab10.023.02 approved: Common Technical Document Bisoprolol hemifumarate 10 mg tablets

Module 1 - Section 3.5 Core SPC, Labelling and Package Leaflet page 9/11

5.2 Pharmacokinetic properties

Bisoprolol is absorbed almost completely from the gastrointestinal tract. Together with the very small first pass effect in the liver, this results in a high bioavailability of approximately 90%. The plasma protein binding of bisoprolol is about 30%. The distribution volume is 3.5 l/kg. The total clearance is approximately 15 l/h. The plasma elimination half-life (10-12 hours) provides 24 hours efficacy following a once daily dosage. Bisoprolol is excreted from the body by two routes, 50% is metabolised by the liver to inactive metabolites which are then excreted by the kidneys. The remaining 50% is excreted by the kidneys in an unmetabolised form. Since elimination takes place in the kidneys and the liver to the same extent, a dosage adjustment is not required for patients with impaired liver function or renal insufficiency. The kinetics of bisoprolol are linear and independent of age. In patients with chronic heart failure (NYHA stage III) the plasma levels of bisoprolol are higher and the half life is prolonged compared to healthy volunteers. Maximum plasma concentration at steady state is 64 ± 21 ng/ml at a daily dose of 10 mg and the half life is 17 ± 5 hours.

5.3 Preclinical safety data

Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity or carcinogenicity. Like other β-blocking agents, bisoprolol caused maternal (decreased food intake and decreased body weight) and embryo/fetal toxicity (increased incidence of resorptions, reduced birth weight of the offspring, retarded physical development) at high doses but was not teratogenic.

6 Pharmaceutical particulars

6.1 List of excipients

Core Microcrystalline cellulose Calcium hydrogen phosphate Pregelatinised maize starch Crospovidone Colloidal anhydrous silica Magnesium stearate

Coating issue date: 07-07-06 version: M135-01.BSL.tab10.023.02 approved: Common Technical Document Bisoprolol hemifumarate 10 mg tablets

Module 1 - Section 3.5 Core SPC, Labelling and Package Leaflet page 10/11

Hypromellose Macrogol 400 Titanium dioxide (E171) Iron oxide yellow (E172) Iron oxide red (E172)

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

2 years in PVC/PE/PVDC/Al blister in Al sachet. 1 year in PVC/PE/PVDC/Al blister without Al sachet and HDPE tablet containers.

6.4 Special precautions for storage

HDPE container: Do not store above 25 °C. Store in the original container Keep the container tightly closed.

PVC/PE/PVDC/AL blister and PVC/PE/PVDC/AL blister in Al sachets: Do not store above 25 °C. Store in the original package

6.5 Nature and contents of the container

Carton boxes with 2, 3, 5, 6 or 10 PVC/PE/PVDC/Al blister packaging of 10 tablets or PVC/PE/PVDC/Al blister packaging in Al sachets of 10 tablets each. Carton boxes with 1, 2 of 4 PVC/PE/PVDC/Al blister packaging of 14 tablets or PVC/PE/PVDC/Al blister packaging in Al sachets of 14 tablets each. HDPE tablet containers containing 30 or 50 tablets. Carton boxes with 50 tablets in EAV blister packaging (PVC/PE/PVDC/Al).

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

No special requirements.

issue date: 07-07-06 version: M135-01.BSL.tab10.023.02 approved: Common Technical Document Bisoprolol hemifumarate 10 mg tablets

Module 1 - Section 3.5 Core SPC, Labelling and Package Leaflet page 11/11

7 Marketing authorisation holder

To be completed nationally

8 Marketing authorisation number(s)

To be completed nationally

9 Date of first authorisation/renewal of the authorisation

To be completed nationally

10 Date of revision of the text

To be completed nationally

issue date: 07-07-06 version: M135-01.BSL.tab10.023.02 approved: